Why Combination Therapy?
For decades, oral medications called PDE5 inhibitors sildenafil (Viagra), tadalafil (Cialis), and others have been the standard of care for erectile dysfunction. They work well for most men. But not everyone achieves a satisfactory result. Some men have partial responses: they get an erection, but it is not hard enough for intercourse. Others have no response at all. And some men simply want a treatment that addresses the underlying cause rather than temporarily managing symptoms.
This is where regenerative therapies enter the picture. Low intensity shockwave therapy (LiSWT), platelet rich plasma (PRP), and stem cell therapy are designed to repair damaged tissue, stimulate new blood vessel growth, and restore natural erectile function. The theoretical advantage is obvious: instead of taking a pill before every sexual encounter, a course of regenerative therapy might produce lasting improvement.
The logical next step is to combine the two approaches. Use PDE5 inhibitors for immediate symptom relief while regenerative therapies attempt to repair the underlying damage. This combination could help men who do not respond fully to either treatment alone.
But does it actually work? A new systematic review and meta analysis by Quistini and colleagues (2025) provides the best available answer. The full text of this study is available here: systematic review and meta-analysis by Quistini and colleagues (2025)
What the New Meta Analysis Found
Quistini and colleagues searched the medical literature and found 1,416 potentially relevant articles. After screening, only eight studies met their strict inclusion criteria. These eight studies included a total of 553 patients. All of the studies compared combination therapy (PDE5 inhibitors plus LiSWT) to monotherapy (either PDE5 inhibitors alone or LiSWT alone). Notably, there were no studies on PRP or stem cell therapy only LiSWT.
The authors measured erectile function using two validated tools: the International Index of Erectile Function 5 (IIEF 5, a 5 question version of the standard scale) and the Erection Hardness Scale (EHS, 1 to 4).
Combination vs PDE5 inhibitor alone. When combination therapy was compared to PDE5 inhibitors alone, there was no statistically significant difference in IIEF 5 scores. In plain English: adding LiSWT to a PDE5 inhibitor did not improve outcomes compared to taking the PDE5 inhibitor by itself.
Combination vs LiSWT alone. When combination therapy was compared to LiSWT alone, there was a statistically significant improvement in IIEF 5 scores. The standardized mean difference (SMD) was 0.61 (95% confidence interval 0.13 to 1.09, p = 0.013). This means that men who received both treatments had better erectile function than men who received only shockwave therapy.
Subgroup analysis vasculogenic ED. In men whose erectile dysfunction was caused by vascular disease (e.g., atherosclerosis from high blood pressure, high cholesterol, or smoking), the combination was even more effective. The SMD was 0.65 (p < 0.001).
Subgroup analysis diabetic ED. The strongest effect was seen in men with diabetes. The SMD was 1.05 (p < 0.001). This is a large effect, suggesting that men with diabetic ED may benefit substantially from adding LiSWT to their PDE5 inhibitor regimen.
Summary of Key Results
| Comparison | SMD (95% CI) | p-value | Clinical interpretation |
| Combination vs PDE5i alone | Not significant | >0.05 | No difference. Adding LiSWT does not help if PDE5i already works. |
| Combination vs LiSWT alone | 0.61 (0.13 to 1.09) | 0.013 | Combination is better than LiSWT alone. |
| Subgroup: vasculogenic ED | 0.65 | <0.001 | Combination is beneficial for men with vascular disease. |
| Subgroup: diabetic ED | 1.05 | <0.001 | Combination is highly beneficial for men with diabetes. |
SMD = standardized mean difference; CI = confidence interval; PDE5i = PDE5 inhibitor; LiSWT = low-intensity shockwave therapy
The Critical Limitation: High Risk of Bias
Before getting excited about these results, we must address a serious problem. The authors themselves state plainly: the risk of bias was high because of the low quality of the studies.
Three Reasons to Interpret These Results Cautiously
- High risk of bias. The authors explicitly rated the quality of the evidence as low because of poor study design. Many of the eight included studies had methodological flaws lack of proper blinding, small sample sizes, inadequate control for confounders. Until larger, well designed trials are conducted, we should treat these findings as hypothesis generating rather than practice changing.
- Small number of studies and patients. Only eight studies with 553 patients were included. This is a modest evidence base, especially when divided into subgroups. The confidence intervals for some estimates are wide, reflecting this uncertainty.
- No data on PRP or stem cells. The title of the paper mentions “regenerative therapies” in general, but the analysis only included LiSWT. There is no high quality evidence on PRP or stem cells for ED something patients should know before paying for these expensive and unproven treatments.
Putting This in Context: What Cochrane Already Told Us
To interpret the Quistini findings correctly, we need to consider them alongside the earlier Cochrane review on LiSWT. The Cochrane systematic review (2025) – the gold standard in evidence synthesis asked a different question: does LiSWT work better than sham (placebo) treatment? Cochrane systematic review (2025) on low-intensity shockwave therapy for erectile dysfunction
The Cochrane review found that LiSWT may have a small effect on erectile function, but the certainty of the evidence was LOW. The average improvement in IIEF EF was 3.89 points in the short term just below the threshold that most men would notice (MCID = 4 points). In other words, LiSWT alone is not a miracle cure.
The Quistini meta analysis adds an important nuance. It does not claim that LiSWT alone is highly effective. Instead, it shows that for men who are already taking PDE5 inhibitors, adding LiSWT may provide additional benefit especially for those with diabetes or vascular disease. However, the combination did not outperform PDE5 inhibitors alone in the overall analysis.
In simple terms: if a PDE5 inhibitor already gives you a rock hard erection (EHS 4), adding LiSWT probably will not help. But if you have a partial response an erection that is not quite hard enough and you have diabetes or vascular disease, adding LiSWT might push you over the threshold to satisfactory function.
Understanding What the Combination Actually Achieves
The Quistini meta-analysis gives us useful information, but it also leaves many questions unanswered. To understand the true value of combination therapy, we need to be clear about both what the study found and what it did not.
| What Quistini et al. demonstrated | What remains unknown |
| Combination (PDE5i + LiSWT) is better than LiSWT alone (SMD 0.61, p=0.013) | Whether combination is better than high-dose PDE5i alone |
| Effect is strongest in diabetic ED (SMD 1.05, p<0.001) | Role of PRP or stem cells zero studies met inclusion criteria |
| Effect is significant in vasculogenic ED (SMD 0.65, p<0.001) | Long-term durability beyond 6-12 months |
| Statistically significant improvement in IIEF-5 scores | Clinical significance for individual patients (SMD 0.61 is moderate) |
| Eight studies with 553 patients included | Optimal treatment protocol (sessions, energy, frequency) |
Interpreting the Subgroup Findings
The subgroup analyses are the most valuable part of this meta-analysis. The overall comparison (combination vs PDE5i alone) showed no difference. But when the authors looked closer, they found that the effect of adding LiSWT depended heavily on the underlying cause of erectile dysfunction.
Why diabetes showed the strongest effect (SMD 1.05). Diabetes damages small blood vessels (microvascular disease) and impairs endothelial function. LiSWT is believed to work by stimulating angiogenesis the growth of new blood vessels. In a diabetic penis, where existing vessels are damaged, the potential for new vessel growth may be greater than in relatively healthy tissue. This biological plausibility supports the statistical finding.
Why vasculogenic ED also responded well (SMD 0.65). This category includes men with atherosclerosis from hypertension, hyperlipidemia, or smoking. The mechanism is similar: damaged blood vessels that may benefit from pro-angiogenic therapy.
Why the overall analysis showed no difference between combination and PDE5i alone. This is because the PDE5i alone group already had relatively good responses. When a treatment works well, there is little room for improvement. Adding LiSWT to an already effective PDE5i regimen is like adding a second sprinkler to a lawn that is already green unnecessary.
Two Key Limitations from the Authors Themselves
The Quistini study is transparent about its weaknesses. The authors state two major limitations that readers must understand.
Limitations Acknowledged by Quistini et al.
- High risk of bias. The quality of the included studies was low. Many lacked proper blinding, had small sample sizes, or used non-standardized protocols. When the underlying studies are flawed, the meta-analysis inherits those flaws.
- No data on PRP or stem cells. Despite the title mentioning “regenerative therapies,” only LiSWT was represented. Patients should know that PRP and stem cell therapy for ED lack high-quality evidence. Clinics offering these treatments at high cost are operating outside the evidence base.
Comparison with the Cochrane Review
The Cochrane review (2025) asked whether LiSWT alone works better than sham. The answer was: a small effect, low certainty evidence, and the improvement may not be clinically noticeable (IIEF-EF improvement of 3.89 points, just below the MCID of 4 points).
The Quistini meta-analysis asks a different question: for men already taking PDE5 inhibitors, does adding LiSWT help? The answer is: it helps compared to LiSWT alone, but not compared to PDE5i alone. The combination is most helpful for men who have a specific cause (diabetes or vascular disease) and a partial response to medication.
These two reviews are complementary, not contradictory.Cochrane tells us LiSWT alone is not a miracle. Quistini tells us combination therapy may help a subset of patients who are not fully responding to PDE5 inhibitors.
Clinical Takeaways
Three Clinical Takeaways from the Quistini Study
- For men with diabetes and partial response to PDE5 inhibitors, adding LiSWT is supported by the best available evidence (SMD 1.05, a large effect).
- For men with vasculogenic ED (hypertension, hyperlipidemia, smoking history) and partial response, combination therapy is also supported (SMD 0.65, a moderate-to-large effect).
- For men who already achieve full, rigid erections (EHS 4) on PDE5 inhibitors alone, adding LiSWT has not been shown to provide any benefit.
What This Means for Clinical Practice
The Quistini meta-analysis does not change the standard algorithm for erectile dysfunction treatment. First-line therapy remains lifestyle modification and PDE5 inhibitors. For men who respond fully, no further treatment is needed.
However, for the subset of men who respond partially especially those with diabetes or documented vascular disease combination therapy with LiSWT is a reasonable consideration. The evidence is not strong (high risk of bias), but the signal is positive, and the safety profile of LiSWT is excellent.
Patients should understand that adding LiSWT does not allow them to stop their PDE5 inhibitors. The studies all continued medication throughout. LiSWT is an adjunct, not a replacement.
They should also understand that PRP and stem cell therapies were not represented in this meta-analysis. No high-quality evidence supports their use for erectile dysfunction. Patients should be skeptical of clinics offering these expensive, unproven treatments.
At Adult & Pediatric Urology (APUMN), we take this evidence into account when counseling patients with partial response to PDE5 inhibitors, particularly those with diabetes or vascular disease.
Author
Gregory S. Parries, M.D., PhD
